The number of patients with hyperlipemia or arteriosclerosis in Japan is said to be as much as thirty million including subjects having no rational symptoms. These disorders are associated with a high risk of highly mortal diseases such as heart infarction and cerebral apoplexy. Even at the present time when the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases have been revised by the Japan Atherosclerosis Society, death due to these diseases ranks high in the causes of death in Japan. Hyperlipemia and arteriosclerosis are significant health problems not only in Japan but also in Europe and the Americas. The drugs which are most widely used at present for prevention and treatment of arteriosclerosis are statin drugs which specifically inhibit hydroxy-3-methylglutaryl coenzyme A (hereinafter abbreviated as HMG-CoA) reductase. Three statin drugs rank in the top ten in worldwide sales of drugs. However, in point of fact, it has been found that these drugs exhibit an effect on prevention of onset in 30%-40% of patients and produce no suppression of cardiovascular diseases or the like in about a half of patients which received treatment with such a drug (“Lifestyle Related Disease” by Tamio Teramoto, Nakayama Shoten, 2001, p. 119).
The reasons why HMG-CoA reductase inhibitors which are currently used as agents for prevention and treatment of arteriosclerosis cannot sufficiently suppress cardiovascular diseases or the like are thought to relate to the fact that the mechanism of onset of arteriosclerosis is complicated, the onset mostly being caused by heredity, diabetes, drugs, and other various factors acting in combination. Therefore, diagnosis and treatment of this disease need to be performed in accordance with the pathology of each patient. Accordingly, there is an urgent desire for the development of a drug having a new mechanism of activities which can be expected to have an effect on suppression of onset of a disorder in the coronary artery or degeneration of a lesion in the coronary artery. However, development of a drug as a substitute for statin drugs has not progressed much until now.
ACAT is an enzyme which catalyzes the introduction of an acyl group into cholesterol, and it is considered to be a target of a drug which is expected to be developed for treatment of statin-resistant arteriosclerosis or tailor-made treatment in accordance with individual pathological conditions. This enzyme has attracted attention for years as an important target molecule of a drug for prevention and treatment of arteriosclerosis, and a number of synthetic ACAT inhibitors have been developed. However, these inhibitors have not yet put into clinical use due to side effects or insufficient effects (Meuwese et al., Curr. Opin. Lipidol., Vol. 17, pp. 426-431, 2006).
It has recently been revealed that ACAT exists in the form of two isozymes, ACAT 1 (expressed in many cells and tissues) and ACAT 2 (expressed specifically in the small intestine and liver), which have different in vivo functions from each other. Therefore, in the development of a new drug targeted at ACAT, the importance of specifying its selectivity is recognized (Chang et al., Acta. Biochim. Biophys. Sin., vol. 38, pp. 151-156, 2006).
It has been found that synthetic agents which were abandoned in the middle of their development have an activity which selectively inhibits ACAT 1 (such as Wu-V-23) or which inhibits both ACAT 1 and ACAT 2 (such as avasimibe and pactimibe) (Farese, Arterioscler. Thromb. Vasc. Biol., vol. 26, pp. 1684-1686, 2006).
Also taking the recently reported results of knockout mice (Bell et al., Arterioscler. Thromb. Vasc. Biol., vol. 27, pp. 1396-1402, 2007) into consideration, there is a strong expectation that a new drug will be developed from the family of selective ACAT 2 inhibitors.
It is reported that pyripyropene A which was already reported as an ACAT inhibitor (Tomoda et al., J. Antibiot. Vol. 47, pp. 148-153, 1994) selectively inhibits ACAT 2 isozyme (Lada et al., J. Lipid Res., vol. 45, pp. 378-386, 2004). However, up to the present time, there has been no research of development of a new drug with a selective ACAT 2 inhibitor as a main active agent.